title: [Domino principle--monoamines in bottom-view].
abstract: One of the first neurobiological theories of major depression was the monoamine deficiency hypothesis. The classic monoamine theory of depression suggested that a deficit in monoamine neurotransmitters in the synaptic cleft was the main and primary cause of depression. Recent and newer versions and modifications of the primary classic theory also mainly included this postulate, while other theories of depression preferred departing from the monoamine-based model altogether. Unfortunately, the clear neurobiology of major depression remains an elusive issue, despite intense research. It is clearly held that most, if not all, antidepressant pharmacotherapies treatments produce their therapeutic antidepressant effects, at least in part, by modulating monoamine systems (noradrenergic, serotonergic, and dopaminergic) by a selective or a multi-acting way; however, much less is known about the neurobiological pathology of these monoamine systems in depression. Much of the past 10-15 years of research in the biology of mood disorders has led to considerable evidence in depression implicating multiple system pathology, including abnormalities of monoamine as well as other neurotransmitter systems. These approaches and findings have led researchers to propose broader theories regarding the neurobiology of depression, just like a spreading disorder of specific neuronal networks in the brain. A model for the pathophysiology of depression ill be discussed in the next pages, after describing the main components of depression pathogenesis. Suggestion is that the primary defect emerges in the cross-regulation and vulnerability of special monoaminergic and non-monoaminergic neural networks, which leads to a decrease in the tonic release of neurotransmitters in their projection areas, altering postsynaptic sensitivity, and following, overexaggerated responses to acute increases in the presynaptic firing rate and transmitter release. It is proposed that the primary defect should be involved, in the noradrenergic innervation spreading from the locus coeruleus (LC). Dysregulation of the LC projection activities may lead in turn to malfunction of serotonergic and dopaminergic neurotransmission. Failure of the LC function could explain the basic impairments in the processing of novel information, intensive processing of irrational beliefs, and anxiety. Consecutive deficits in the serotonergic neurotransmission may contribute to the mood changes and reduction in the mesotelencephalic dopaminergic activity to loss of motivation, and anhedonia. Malfunction and dysregulation of CRF and other neuropeptides such as neuropeptide Y, galanin and substance P may reinforce the LC dysfunction and thus further weaken the adaptive ability to stressful stimuli. The new SNRI antidepressants seem to be more superior and effective in the treatment of major depression and in the prophylaxis of recurrent depressive episodes because of their coexistent noradrenergic activity.
authors.affiliation: Vas Megyei Markusovszky Kórház ZRt., Pszichiátriai Osztály. sumegia@gmail.com
authors.forename: András
authors.initials: A
authors.lastname: Sümegi
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015306:Biogenic Monoamines / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003863:Depression / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D019004:Galanin / Q000378:metabolism; D006801:Humans; D008125:Locus Coeruleus / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D011903:Raphe Nuclei / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013373:Substance P / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D003346:Corticotropin-Releasing Hormone; D018765:Dopamine Uptake Inhibitors; D019004:Galanin; D009478:Neuropeptide Y; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D009638:Norepinephrine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013373:Substance P